{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:21:13Z","timestamp":1789150873539,"version":"build-2803163510"},"reference-count":27,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T00:00:00Z","timestamp":1719532800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:p>Alnuctamab, a B\u2010cell maturation antigen (BCMA)\u2010targeting T\u2010cell engager, has demonstrated encouraging antitumor activity in the phase I study CC\u201093269\u2010MM\u2010001 treating patients with relapsed or refractory multiple myeloma. Identification of a recommended Phase III dose (RP3D) was a key objective, as such population pharmacokinetic (PopPK) and exposure\u2013response analysis was critical. Intravenous (IV) alnuctamab was administered in fixed doses (0.15\u201310\u2009mg) or in step\u2010up doses to a maximum 10\u2010mg target dose. Subcutaneous (SC) step\u2010up doses of 3 and 6\u2009mg were followed by a target dose range of 10\u201360\u2009mg. Concentration data from IV and SC alnuctamab administration was pooled and was well described by a two\u2010compartment PopPK model with first\u2010order absorption and elimination. Covariate analysis determined that the inclusion of baseline soluble BCMA (sBCMA) on clearance significantly improved model fitting. Individual exposure parameters were estimated from the final model to characterize exposure\u2013response relationships. Switching from IV to SC administration improved the safety profile of alnuctamab by limiting the frequency of grade \u22652 CRS events. A significant exposure\u2013CRS relationship was observed after the first SC dose, but not subsequent dose administrations. Exposure\u2013safety analysis did not find a statistically significant relationship between increasing exposure and the probability of key safety events of interest. Logistic regression analysis for patients administered SC alnuctamab identified that increased exposure significantly increased the probability of response, although the additional benefit was minimal at exposures above 30\u2009mg target dose. Considering the totality of exposure\u2013response data, the clinical pharmacology assessment supported a SC RP3D of 3\/6\/30\u2009mg.<\/jats:p>","DOI":"10.1002\/cpt.3353","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T07:44:46Z","timestamp":1719560686000},"page":"866-874","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Informing the Recommended Phase III Dose of Alnuctamab, a <scp>CD3<\/scp>\u2009\u00d7\u2009<scp>BCMA<\/scp> T\u2010Cell Engager, Using Population Pharmacokinetics and Exposure\u2013Response Analysis"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4214-7524","authenticated-orcid":false,"given":"Brian","family":"Kiesel","sequence":"first","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu","family":"Osawa","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8181-8848","authenticated-orcid":false,"given":"Madhan","family":"Masilamani","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merav","family":"Bar","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Hsu","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Godwin","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Burgess","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Lamba","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7677-5927","authenticated-orcid":false,"given":"Allison","family":"Gaudy","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,28]]},"reference":[{"key":"e_1_2_11_1_1","unstructured":"U.S. Department of Health and Human Services. 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